Constipation is generally defined as infrequent and difficult passage of stool. Medical reporting estimates that one of every 50 people in the United States suffers from constipation. That is, one of the most common disorders among Americans. Constipation is more likely to affect females than males and more likely to occur in older adults, showing an exponential increase after the age of 65. The actual occurrence of constipation is likely higher than reported, as many individuals suffer at home without seeking professional care.
Although in some instances constipation may be caused by obstruction, most constipation can be associated with factors such as a diet low in soluble and insoluble fibers, inadequate exercise, medication use (in particular, opiate analgesics, anticholinergic antidepressants, antihistamines, and vinca alkaloids), bowel disorders, neuromuscular disorders, metabolic disorders, poor abdominal pressure or muscular atony.
A precise quantitative definition of constipation has been difficult to establish due to the wide range of perceived “normal” bowel habits, as well as the diverse array of symptoms and signs associated with constipation. The FDA has recognized a need for prescriptive treatment of occasional constipation.
Prostaglandins (hereinafter, referred to as PGs) are members of class of organic carboxylic acids, which are contained in tissues or organs of human or other mammals, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A):

PGs are classified into several types according to the structure and substituents on the five-membered ring, for example,    Prostaglandins of the A series (PGAs);
    Prostaglandins of the B series (PGBs);
    Prostaglandins of the C series (PGCs);
    Prostaglandins of the D series (PGDs);
    Prostaglandins of the E series (PGEs);
    Prostaglandins of the F series (PGFs);
and the like. Further, they are classified into PG1s containing a 13,14-double bond; PG2s containing, 5,6- and 13,14-double bonds; and PG3s containing 5,6-, 13,14- and 17,18-double bonds. PGs are known to have various pharmacological and physiological activities, for example, vasodilatation, inducing of inflammation, platelet aggregation, stimulating uterine muscle, stimulating intestinal muscle, anti-ulcer effect and the like. The major prostaglandins produced in the human gastrointestinal (GI) system are those of the E, I and F series (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management. (WB Saunders Company, 1998); Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Hawkey, et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart, et al., Gastroenterology, 109: 285-301 (1995)).
Under normal physiological conditions, endogenously produced prostaglandins play a major role in maintaining GI function, including regulation of intestinal motility and transit, and regulation of fecal consistency. (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management. (WB Saunders Company, 1998); Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Hawkey, et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart, et al., Gastroenterology, 109: 285-301 (1995); Robert, Adv Prostaglandin Thromboxane Res, 2:507-520 (1976); Main, et al., Postgrad Med J, 64 Suppl 1: 3-6 (1988); Sanders, Am J Physiol, 247: G117 (1984); Pairet, et al., Am J Physiol., 250 (3 pt 1): G302-G308 (1986); Gaginella, Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990)). When administered in pharmacological doses, both PGE2 and PGF2α have been shown to stimulate intestinal transit and to cause diarrhea (Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Robert, Adv Prostaglandin Thromboxane Res, 2:507-520 (1976)). Furthermore, the most commonly reported side effect of misoprostol, a PGE1 analogue developed for the treatment of peptic ulcer disease, is diarrhea (Monk, et al., Drugs 33 (1): 1-30 (1997))
PGE or PGF can stimulate the intestines and cause intestinal contraction, but the enteropooling effect is poor. Accordingly, it is impossible to use PGEs or PGFs as cathartics because of side effects such as stomachache caused by the intestinal contraction.
Multiple mechanisms, including modifying enteric nerve responses, altering smooth muscle contraction, stimulating mucous secretion, stimulating cellular ionic (in particular electrogenic Cl− transport) and increasing intestinal fluid volume have been reported to contribute to the GI effects of prostaglandins (Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Hawkey, et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart, et al., Gastroenterology, 109: 285-301 (1995); Robert, Adv Prostaglandin Thromboxane Res, 2:507-520 (1976); Main, et al., Postgrad Med J, 64 Suppl 1: 3-6 (1988); Sanders, Am J Physiol, 247: G117 (1984); Pairet, et al., Am J Physiol, 250 (3 pt 1): G302-G308 (1986); Gaginella, Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990); Federal Register Vol. 50, No. 10 (GPO,1985); Pierce, et al., Gastroenterology 60 (1): 22-32 (1971); Beubler, et al., Gastroenterology, 90: 1972 (1986); Clarke, et al., Am J Physiol 259: G62 (1990); Hunt, et al., J Vet Pharmacol Ther, 8 (2): 165-173 (1985); Dajani, et al., Eur J Pharmacol, 34(1): 105-113 (1975); Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management 1451-1471 (WB Saunders Company, 1998)). Prostaglandins have additionally been shown to have cytoprotective effects (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management. (WB Saunders Company, 1998); Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Robert, Adv Prostaglandin Thromboxane Res 2:507-520 (1976); Wallace, et al., Aiiment Pharmacol Ther 9: 227-235 (1995)).
U.S. Pat. No. 5,317,032 to Ueno et al. describes prostaglandin analog cathartics, including the existence of bicyclic tautomers of the same and U.S. Pat. No. 6,414,016 to Ueno describes bicyclic tautomers of a prostaglandin analog as having pronounced activity as anti-constipation agents. The bicyclic tautomers of a prostaglandin analog, which is substituted at the C-16 position by one or more halogen atoms, especially fluorine atoms, can be employed in small doses for relieving constipation.
U.S. Patent publication No. 2003/0130352 to Ueno et al. describes that prostaglandin compound opens and activates chloride channels, especially ClC channels, more especially ClC-2 channel.
U.S. Patent publication No. 2003/0119898 to Ueno et al. describes specific composition of a halogenated prostaglandin analog for the treatment and prevention of constipation.
U.S. Patent publication No. 2004/0138308 to Ueno et al. describes that a chloride channel opener, especially a prostaglandin compound can be used for the treatment of abdominal discomfort, and for the treatment of functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia.
MiraLax™ (polyethylene Glycol 3350, NF Powder for solution) is synthetic polyglycol having an average molecular weight of 3350, and used for the treatment of occasional constipation. This product is basically used for up to two weeks. Prolonged, frequent or excessive use of MiraLax™ may result in electrolyte imbalance and dependence on laxatives (MiraLax™ Package insert). MiraLax™ acts as an osmotic agent, which creates an imbalance in the lumen of the gut and draws fluid osmotically into the lumen. The increased fluid level softens the stool and promotes bowel movements.
Likewise, the aforesaid ClC-2 chloride channel activators are believed to function by stimulating chloride secretion into the lumen of the gut, which draws water through an osmotic mechanism into the lumen that, in turn, promotes bowel movements. Given that a specific prostaglandin compound is an ion channel activator and is believed to work essentially in an osmotic manner, like Miralax™, one would expect that long term use of said prostaglandin compound would also have the disadvantages found in MiraLax™. Therefore, its use would be limited practically to a couple of weeks, just like Miralax™.
Zelnorm® (tegaserod maleate) is indicated for the short-term treatment of women with irritable bowel syndrome (IBS), whose primary bowel symptom is constipation. In two randomized, placebo-controlled, double-blind studies enrolling 288 males, there were no significant differences between placebo and Zelnorm® response rates. The safety and effectiveness of Zelnorm® in men with IBS with constipation has not been established. In addition, Subgroup analyses of patients aged 65 years and older showed no significant treatment effect for Zelnorm® over placebo. That is, the effectiveness of Zelnorm® in patients aged 65 years and older with chronic idiopathic constipation has not been established. Further, if the patients stop taking Zelnorm®, the symptoms may return within 1 or 2 weeks. (Zelnorm® Package insert)